IgM and IgD positive naive B cells, which reacted with a normal T cell-dependent antigen, will move to splenic red pulp and bridging channel and proliferate there to form extrafollicular foci in an early stage of immune response. Plasmablast will proliferate in the extrafollicular foci and undergo differentiation into antibody-producing cells so as to eliminate an antigen. Most of the antibody-producing cells generated in the early stage will have a short life span, while a part of them will induce class-switching into IgG class and the like. A part of B cells that has reacted with an antigen will proliferate in follicle and form a germinal center. B cells will accumulate point mutations in their immunoglobulin V-region during the germinal center reaction so as to increase their affinity for the antigen. Most of B cells in the germinal center will induce the class-switching. The antibody-producing cells that have gone through the above germinal center reaction will bear the production of antibodies thereafter. A part of B and T lymphocytes that were activated by antigen-stimulation in a first immune response will grow into memory lymphocytes. Memory B cells will be generated from a part of the germinal center B cells. The memory lymphocytes will survive for a long period of time. When being exposed to the same antigen, the memory lymphocytes will proliferate more rapidly than the naive B cells and form a huge foci of plasmablasts and plasma cells in the splenic red pulp and bridging channel, resulting in a rapid and large-scale production of antibodies. Vaccine will defend against infection by inducing immune memory.
B cell antigen-receptor (BCR) consists of a membrane-type immunoglobulin and signal component Igα/Igβ molecules. Upon the reaction with the antigen, BCR will intracellularly transduce a signal through the Igα/Igβ molecules (class II antigen). Coreceptors of BCR such as CD19, CD22, CD72 and FcγR2B modulate an appropriate threshold for signaling by positively or negatively regulating BCR signal transduction (signaling), so that they will have an influence on determination of the fate of B cells such as proliferation, differentiation into the antibody-producing cells, non-response or apoptosis. Among them, CD22 is known as a molecule that will down-modulate the BCR signaling. Three immune receptor tyrosine-based inhibition motifs (ITIM) existing in an intracellular region of CD22 will be phosphorylated directly after BCR crosslinking has occurred, and CD22 will recruit a phosphatase, Src-homology domain 2 (SH2)− containing protein tyrosine phosphatase-1 (SHP− 1) near BCR so as to activate it and negatively regulate the BCR signaling.
The memory B cells will be generated through the differentiation mainly from cells that have been class-switched into IgG, and express the membrane-type IgG as the BCR. IgG-BCR will transduce a signal through the Igα/Igβ molecules like IgM-BCR and IgD-BCR expressed by the naive B cells. Recently, a finding has been obtained that the IgG-BCR is involved in the rapid response of the memory B cells (Wakabayashi, C., et al., Science, 2002, 298(5602): p. 2392-5). Goodnow et al. made a transgenic mouse in which almost all of the B cells expressed IgG specific for HEL, and analyzed an immune response of IgG-positive naive B cells. They revealed that the IgG-positive naïve B cells would rapidly proliferate upon the antigen stimulation similarly in the case of the memory immune response, so that they would form a huge foci of the plasmablast and produce a large amount of antibodies (Martin, S. W. and C. C. Goodnow, Nat Immunol. 2002, 3(2): p. 182-8). These results show that the IgG-BCR has a function different from the IgM-BCR or IgD-BCR, and is involved in a rapid activation of B cells in the memory response.
On the other hand, the present inventors found that while the IgM-BCR or IgD-BCR were negatively regulated by CD22, the IgG-BCR would not be regulated by CD22 so that it could induce an effective signaling (Wakabayashi, C., et al., Science, 2002. 298(5602): p. 2392-5).
[Non Patent Document 1] Nitschke, L. and T. Tsubata, Trends Immunol, 2004. 25(10): p. 543-50
[Non Patent Document 2] Tedder, T. F., et al., Annu Rev Immunol, 1997. 15: p. 481-504.